This research project involves neurophysiological, pharmacological, anatomical, behavioral and clinical approaches to elucidating the properties of an intrinsic analgesia producing system. We are particularly interested in a single neuron analysis of the mid-brain periaqueductal (PAG), the medullary nucleus raphe magnus (NRM) and the spinal cord. The firing of these neurons in response to local or systemic opiates is being studied. The effect of discrete lesions of brainstem and spinal cord on the analgesic efficacy of opiates is also being studied to determine the relative contribution of enkephalins and opiate receptors in different brain regions. We have shown that the PAG produces analgesia at least partially by activating caudal medullary neurons which project to the spinal cord. The properties of these caudal medullary neurons are the subject of ongoing studies. Human studies are taking a parallel course. Using postoperative pain as a model, we have provided some evidence that the intrinsic analgesia system is endorphin mediated and have begun to study the factors leading to its activation.